tbuckley/cabot-search huggingface dataset:
Evaluating surgical treatment options for small nonfunctional pancreatic neuroendocrine tumors in the NCDB.
Authors: Toshitaka Sugawara, Salvador Rodriguez Franco, Michael Kirsh, Kathryn Colborn, Jun Ishida, Samuele Grandi, Mohammed Al-Musawi, Ana Gleisner, Richard D. Schulick, Marco Del Chiaro
Journal: Journal of Clinical Oncology (2023)

645 Background: The role of surgery for small (≤2 cm), nonfunctional pancreatic neuroendocrine tumors (NF-PNETs) remains controversial due to the wide range of tumor aggressiveness. Consensus guidelines of the US, Europe, and Japan offer different recommendations for treatment of small NF-PNETs. The objective of this study is to evaluate the survival benefit of surgical resection for small NF-PNETs. Methods: Patients with NF-PNETs were identified in the National Cancer Database from 2004 to 2018. Small NF-PNETs were divided into two groups: group 1a (tumor ≤1 cm) and group 1b (tumor 1.1 – 2.0 cm). Cox regression models were used to compare the overall survival between resected and unresected small NF-PNETs patients. Interactions between preoperative factors and surgery were estimated using subgroup analyses. Results: We identified 1,278 patients in group 1a and 3,363 patients in group 1b. After adjusting for preoperative factors, surgery was associated with longer survival for patients in group 1b (HR, 0.58; 95% CI, 0.42–0.80; P &lt;0.001), but not for patients in group 1a (HR, 0.68; 95% CI, 0.41–1.11; P = 0.122). Interaction analysis found that age younger than 65 years, fewer comorbidities, treatment at academic institutions, distal pancreatic tumors, and clinical lymph node metastasis were factors associated with longer survival in group 1b by surgery. Conclusions: Findings from this large study support surgical resection for some patients with NF-PNETs (1.1 – 2.0 cm). This, of course, must be taken in context with the patient’s clinical situation. Based on data available for analysis in this study, resection for subcentimeter NF-PNETs does not appear to be of general benefit, but should also be investigated in the context of Ki-67 index.[Table: see text]
Impact of <i>KRAS </i>mutation variants on clinicopathological features and outcomes in patients with metastatic pancreatic adenocarcinoma.
Authors: Chirag Patel, Wei Sha, Mohamed E. Salem, Laura W. Musselwhite, Jimmy J. Hwang, Kunal C. Kadakia
Journal: Journal of Clinical Oncology (2023)

749 Background: Most pancreatic ductal adenocarcinoma (PDAC) exhibit KRAS mutations. A subset of PDACs harbor KRAS wild-type (WT) and appear to carry better prognosis. Given the recent development of KRAS G12C inhibitors, it is imperative to better understand KRAS variants in contemporary cohorts. Herein, we characterized the prevalence of the different KRAS variants and its impact on clinicopathological features and outcomes. Methods: A retrospective review of patients with metastatic PDAC and a known KRAS mutation status who underwent next-generation sequencing (NGS) from liver biopsy was performed. Descriptive statistics analyzed the differences in clinicodemographic features by presence and type or absence of KRAS variants. Kaplan-Meier method was used to assess overall survival (OS). Cox regression was used to study the relationship between KRAS variants and OS when confounding factors were adjusted. Results: 50 pts with PDAC diagnosed at a single community-based institution between 2011-2018 were evaluated. Median age at diagnosis was 68 years (24-80 range), 68% were male, and 76% presented with metastases. Most (86%) tumors harbored KRAS mutations. The most frequent variants were G12V (44%), G12D (37%), G12R (9%), Q61R (5%), G12C (2%), Q61H (2%). Sex (p=0.03) and tumor differentiation (p=0.04) varied according to mutation status and KRAS variant subtype. However, no significant difference was observed in age, race, smoking status, location of primary, and performance status (PS) in KRAS variants. Overall, median OS in months was 8.9 (95% CI 6.7-14.3) for KRAS mutated patients and 11.2 (95% CI 2.1-33.5) for patients with WT. Among patients with KRAS mutations, median OS in months by variant was as following: G12V 9.6 (95%CI 6.6-17.2), G12D 8.4 (95%CI 3.9-15.4), G12R 8.2 (95%CI 1-20.8), and Q61R 11.8 (95%CI 1.3-22.3). However, these differences did not reach statistical significance (p=0.72). In multivariable analyses, female sex (HR 0.16, 95% CI 0.03-0.81, p=0.03) and no receipt of chemotherapy (38.5 95% CI 2.1-698.50, p=0.01) were significant predictors of death. KRAS mutation variant type was not an independent predictor of death. Conclusions: No significant difference was observed in metastatic PDAC with KRAS mutations compared to WT. However, numerical difference in OS were observed among the various KRAS mutation type. Hence, larger studies are needed to better define the effect of KRAS type on outcomes.
Clinical therapeutic effects of neoadjuvant chemotherapy in resectable pancreatic cancer.
Authors: Masaaki Murakawa, Daishi Takahashi, Shinnosuke Kawahara, Yuto Kamioka, Naoto Yamamoto, Shun Tezuka, Satoshi Kobayashi, Makoto Ueno, Manabu Morimoto, Takashi Oshima, Norio Yukawa, Yasushi Rino, Soichiro Morinaga
Journal: Journal of Clinical Oncology (2023)

677 Background: Results from the phase III Prep-02/JSAP-05 trial demonstrated the efficacy and safety of gemcitabine plus S-1 as neoadjuvant chemotherapy for resectable pancreatic cancer. However, consensus on neoadjuvant chemotherapy for pancreatic cancer has not yet been established, and the effects of neoadjuvant therapy on clinical features of the tumor and improvement in prognosis have not been fully investigated. We aimed to investigate the effect of neoadjuvant chemotherapy on resectable pancreatic cancer. Methods: Between 2013 and 2021, 291 patients who underwent curative resection for resectable pancreatic cancer at our hospital were enrolled. The patients were categorized into groups of those who received neoadjuvant chemotherapy (NAC group: n = 91) and those who received up-front surgery (US group: n = 200). Prognostic predictors were examined in (i) all patients, (ii) US group, and (iii) NAC group. Statistical significance was considered at p &lt; 0.05. Results: The median follow-up periods were 20.7 and 33.2 months in the NAC and US groups, respectively. In the NAC group, 84 of the 91 patients (94.5%) received gemcitabine-based chemotherapy, and three (3.3%) received chemoradiotherapy. There was no difference in overall survival (OS) and recurrence free survival (RFS) between the two groups. In the background, the NAC group had lower preoperative CA19-9 levels, lower lymph node ratio (LNR), and smaller tumor size than in the US group. During multivariable analysis of OS, preoperative CA19-9 levels, LNR, modified Glasgow prognostic score (mGPS), resection margin, and tumor size were identified as possible prognostic predictors in all patients and in the US group, whereas LNR and mGPS were identified in the NAC group. Conclusions: The prognostic significance of preoperative CA19-9 level, tumor size, and LNR were counteracted in the NAC group. These findings may indicate the effect of neoadjuvant chemotherapy for resectable pancreatic cancer.
Regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy-resistant MSS metastatic colorectal cancer (mCRC).
Authors: Marwan Fakih, Jaideep Singh Sandhu, Dean Lim, Sierra Li, Chongkai Wang
Journal: Journal of Clinical Oncology (2023)

110 Background: We recently reported on the activity of regorafenib (R), ipilimumab (I) and nivolumab (N) (RIN) in microsatellite stable (MSS) mCRC. Here, we describe mature efficacy data at the recommended phase 2 dose (RP2D) and the results of a new escalation (ESC) cohort of 40 mg to 80 mg regorafenib. Methods: Patients (pts) with chemotherapy resistant MSS mCRC received RIN at (R) at 80 mg QD x 21 days in 4-week(w) cycle, (I) at 1mg/kg Q6w and (N) at 240 mg Q 2w. If no more than 1 dose limiting toxicity (DLT) was noted in 6 evaluable pts, an expansion cohort was assessed at that dose level. Following RP2D establishment and given the increased rate of transient skin toxicity on cycle (C) 1, the protocol was amended to explore a 10-pt cohort with 40 mg/day (R) on C1 with escalation to 80mg/day on C2+. Results: 39 pts with chemotherapy resistant MSS mCRC were enrolled. 29 pts enrolled on the RP2D and 10 pts at the amended 40 to 80mg cohort. At the RP2D and ESC cohorts, 7 and 3 pts had liver metastases (LM), respectively. No significant clinical activity was noted in LM pts (ORR = 0%, median progression free survival (mPFS) = 2 months (mo)). Overall response rate (ORR), disease control rate (DCR), mPFS, median overall survival (OS) in the 22 pts with non-LM (NLM) pts in the RP2D and ESC cohorts were 36% (41% iRECIST), 68% (82% iRECIST), 5.0 mo (6.0 mo iRECIST), &gt; 22 mo (not reached) and 0%, 57% (71.4% iRECIST), 4 mo (4 mo iRECIST), and &gt; 10 mo (not reached). 6/22 NLM at the P2RD remain without PD at 22 mo and beyond. All 7 NLM pts in the ESC cohort progressed by 7 mo from enrollment. ctDNA (Guardant 360) assays were available at baseline and at 4-6 weeks in 23/39 pts. Early ctDNA clearance was confirmed in 8/17 pts at RP2D (4PR and 4SD &gt; 6 mo; mPFS = 11 mo) and 2/6 pts at the ESC cohort (PFS 4.5 mo and 7mo). An ESC vs. RP2D strategy mitigated skin rash (10% vs. 38% grade (G) 3; 20% vs. 66% any G). Other immune related ≥ G3 toxicities are summarized. Conclusions: RIN (80/1/240) has substantial activity in MSS NLM mCRC patients. An ESC strategy of 40/1/240 to 80/1/240 on C2+ reduced transient skin rash and other immune-mediated toxicities but was associated with less favorable clinical outcome. These data suggest that a starting R dose of 80 mg is important in priming the immune response to RIN. The RP2D of 80/1/240 mg is recommended for further investigation in NLM mCRC. Clinical trial information: NCT04362839 . [Table: see text]
Do nonoperative modality (NOM) treatments of rectal cancer compromise the chance of cure? Final surgical salvage results from OPERA phase 3 randomised trial (NCT02505750).
Authors: Arthur Sun Myint
Journal: Journal of Clinical Oncology (2023)

6 Background: Watch and wait strategy without surgery for rectal cancer is gaining popularity as it avoids a stoma. We set up an OPERA trial to evaluate the role of radiation dose escalation using Contact X-ray brachytherapy [CXB] (Papillon). We report on the final surgical salvage results for local failures of non-surgical approach. Methods: OPERA is a European phase 3 randomised trial between (Arm A-standard arm)EBCRT 45Gy/25/5weeks with oral capecitabine 825mg/m 2 and EBRT boost of 9Gy/5/5 days randomised against experimental arm (Arm B) EBCRT followed by CXB boost (90 Gy/3/4 weeks). Patients were assessed at 14, 20 and 24 weeks. Watch &amp; wait policy was adopted for patients with cCR and surgery (TME or local excision) offered for residual disease or recurrence after cCR. Results: From July 2015 –June 2020, 148 patients were randomised of which 141 were evaluable. Median age was 68 years and 88 (61%) patients were males. There were 69 patients in Arm A (standard of care with EBRT boost) and 72 patients in Arm B (experimental with CXB boost). All patients received the protocol stratified radiation dose. Median follow-up was 38.2 months (95% CI:34.2-42.5). Clinical complete response (cCR) was observed in 44/69 (64%) in Arm A and 66/72 (92%) in Arm B at 24 weeks (p&lt; 0.001). Surgery was carried out in 66/141 (47%) with suspected residual tumour or local regrowth after achieving cCR. Total 39/66 (59%) patients had TME surgery. Local excision was carried out in 27 /49(41%). Our primary endpoint of organ preservation (OP) rate was 59% (95% CI: 48-72) in Arm A vs. 81% (95% CI: 72-91) in Arm B (HR 0.36, 95% CI: 0.19-0.70; P= 0.0026). When comparing A1(&lt;3cm) vs. B1(&lt;3cm), OP rate was 63% vs. 97% respectively (HR: 0.072, 95% CI 0.0093-0.57; P= 0.0123]). Overall TME free overall survival was 57% for Arm A and 79% for Arm B (HR 0.37,95% CI 0.2-0.71; P=0.0026). Conclusions: OPERA data at 38 months suggest that non-surgical treatment for cT2-cT3a-b rectal cancer is feasible and those who needed surgery for local failures can be salvaged without compromising their chance of cure. There is significant improvement in OP rate for rectal cancer &lt;3cm to start with CXB followed by EBCRT. This option should be discussed with patients wishing to avoid surgery and a stoma as an initial treatment. Clinical trial information: NCT02505750 . [Table: see text]
Clinical and radiological response to locoregional and systemic treatments in well-differentiated gastroenteropancreatic neuroendocrine tumors with liver metastases treated at a reference center in Mexico.
Authors: Cesar Arce Sandoval, Mónica Isabel Meneses Medina, Miriam Heidi Cisneros Cordero, Jorge Humberto Hernandez-Felix, Vanessa Rosas Camargo, Lucero Itzel Torres Valdiviezo, Rixci Ramirez, Jesus Alejandro Gabutti Thomas, Fidel David David Huitzil Melendez
Journal: Journal of Clinical Oncology (2023)

644 Background: liver metastases (LM) from well-differentiated gastroenteropancreatic neuroendocrine tumors (wd-GEP-NET) can develop in 28-77% of patients (pts) in their lifetime. Multiple treatments can provide radiological and symptomatic response. Our aim was to evaluate responses to locoregional (LRT) and systemic (SYST) treatments in wd-GEP-NET with LM. Methods: we included consecutive records of pts with confirmed histological diagnosis of wd-GEP-NET and radiological LM, treated at our institution between 2008-2019. Relevant variables were retrospectively extracted from electronic records. Radiological response was assessed with RECIST 1.1 by radiological independent review. Results: 55 pts, 45.5% male. Median age at LM diagnosis 49 years (IQR 41-63). Primary tumor sites: 49% pancreatic, 27.3% small intestine, 11% unknown, 12.7% others. WHO 2019 grade 1, 2 and 3 in 52.7, 41.8 and 1.8%, respectively. Twentynine tumors (52.7%) were functional, with carcinoid syndrome in n20. At LM diagnosis, 91% of pts had symptomatic disease: hormonal n8, local n4, systemic n4, hormonal + local n4, local + systemic n22, hormonal + systemic n5, hormonal + local + systemic n5. LM tumoral burden was &lt;10% in 22%, 11-50% in 43.6, &gt; 50% in 30.9% of pts. 49.1% of pts had extra hepatic metastatic disease. LRT to LM was administered to 32 pts: TAE/TACE n26, ablation n8. SYST to 22 pts: somatostatin analog n15, Lutetium-177 n4, chemotherapy n2, everolimus n1. 1 pt did not receive treatment. Response to treatments is shown. In the LRT group, -- pts developed complications: n16 postembolization syndrome, n2 infections, n3 liver failure, n7 others. There was 1-procedure-related death. Conclusions: Patients treated with LRT at our institution achieved similar efficacy and safety results compared to those reported by previous studies.[Table: see text]
Phase 1 dose-finding trial of cabozantinib (cabo) and trifluridine/tipiracil (FDT/TPI) in metastatic colorectal carcinoma (mCRC).
Authors: Farshid Dayyani, Jasmine Balangue, Jennifer Brooke Valerin, Jason A. Zell, Thomas H Taylor, May Thet Cho
Journal: Journal of Clinical Oncology (2023)

98 Background: Salvage treatments for refractory mCRC are an unmet need. This study determined the safety and Recommended Phase 2 Dose (RP2D) of the multi-kinase inhibitor Cabo in combination with FDT/TPI in mCRC. Methods: Single institution investigator-initiated phase 1 study using 3+3 design. Patients (pts) with mCRC previously treated with a fluoropyrimidine, oxaliplatin, irinotecan and appropriate biologics were eligible. Cabo was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth factors were allowed. The primary endpoint was Dose Limiting Toxicity (DLT) at 28 days. Secondary endpoints included overall survival (OS), progression-free survival (PFS), objective response rate and CEA response. Results: 12 pts were enrolled. Median age 57 years (31-80), male (9/12), ECOG 0/1 = 7/5, Caucasian/Hispanic/Asian = 7/4/1. 3 pts were treated at DL 0 with no observed DLT. Another 9 pts (n = 6 pts to determine RPD2 and additional n = 3 pts in expansion) were treated at DL 1, none exhibiting a DLT. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%) and rash (25%). G3-4 TRAE in &gt; 5% of patients were neutropenia (25%) and thrombocytopenia, hypokalemia, weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS and OS were 4.1 (95% CI 1.9-6.8) and 6.7 (95% CI 2.2-not evaluable) months, respectively. The disease control rate was 75%. 5/12 (42%) pts had a CEA decline &gt; 30%. Conclusions: The combination of Cabo and FTD/TPI is feasible and tolerable and showed encouraging clinical activity in refractory mCRC. Additional pts are being enrolled at DL 1 and will be presented at the meeting. Clinical trial information: NCT04868773 .
Effect of EGFR and ERBB2 amplifications and activating alterations on efficacy of lenvatinib in hepatocellular carcinoma.
Authors: Mir Lim, Dong Yang, Robin John Lester Imperial, Umair Majeed, Jill Tsai, Joseph Wang Franses, David Hsieh
Journal: Journal of Clinical Oncology (2023)

600 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is associated with a high mortality burden. Lenvatinib is an effective frontline tyrosine kinase inhibitor for HCC but is associated with primary and acquired resistance in most patients. Molecular mechanisms of resistance to lenvatinib remain unclear. Methods: We retrospectively analyzed 227 patients with HCC who underwent baseline ctDNA profiling as a component of routine clinical care, including 46 patients who had serial ctDNA analysis done at baseline and after progression to lenvatinib or ICI. Clinical data including demographics, treatment history, tumor responses, and survival outcomes were abstracted from the electronic medical record. Tumor response was categorized according to RECIST 1.1. A national registry of HCC that underwent ctDNA testing using Guardant360 was analyzed to determine the prevalence of EGFR/ERBB2 alterations in HCC. Results: Nearly a third of patients who progressed on lenvatinib demonstrated a gain in EGFR/ ERBB2 amplifications or activating mutations. No consistent trend in EGFR/ ERBB2 amplifications and alterations was found among ICI refractory HCC. Disease control rates (including complete response, partial response, and stable disease) were 20% in EGFR/ERBB2 altered HCC treated with lenvatinib, 62.5% in EGFR/ERBB2 wildtype HCC treated with lenvatinib (p = 0.05), and 58% in EGFR/ERBB2 altered HCC treated with ICIs (p = 0.09). PFS was also longer in EGFR/ERBB2 wildtype HCC treated with lenvatinib (5.9 months) and EGFR/ERBB2 altered HCC treated with ICIs (7.1 months) compared to EGFR/ERBB2 altered HCC treated with lenvatinib (2.2 months, p = 0.002). In a national cohort of 1739 patients with HCC, EGFR amplifications and activating mutations occurred in 6.5% and 1.5% of cases, respectively, and ERBB2 amplifications and activating mutations occurred in 1.9% and 0.7% of cases, respectively. Among EGFR/ERBB2 mutations, we identified recurrent gatekeeper mutations, including multiple A547T and T790M mutations, in 31% of patients. Conclusions: Our study substantiates EGFR/ERBB2 amplifications and mutations as putative drivers of lenvatinib resistance in patients with HCC and identifies the genetic mechanisms for EGFR pathway activation in refractory cancers. EGFR/ERBB2 alterations may thus represent predictive and pharmacodynamic markers of lenvatinib resistance. These findings lend support to the use of EGFR inhibitors combined with lenvatinib in previously untreated or lenvatinib refractory cancers.
Integrating patient-reported-outcomes into prognostication in gastroesophageal cancer: Results of a population-based retrospective cohort analysis.
Authors: Thais Baccili Cury Megid, Divya Sharma, Lucy Xiaolu Ma, Xin Wang, Carly C. Barron, Raymond Woo-Jun Jang, Carol Jane Swallow, Aruz Mesci, Jonathan Yeung, Rebecca KS Wong, Eric Xueyu Chen, Savtaj Singh Brar, Patrick Veit-Haibach, John Kim, Yvonne Bach, Hiroko Aoyama, Elena Elimova
Journal: Journal of Clinical Oncology (2023)

320 Background: Patient reported outcomes (PRO) measures are accurate self-reflections of an individual’s physical functioning and emotional well-being. The prognostic value is unknown in gastroesophageal (GE) cancer patients (pts). The Edmonton Symptom Assessment Scale (ESAS) is a simple and validated 10-item PRO tool which uses a 0 to 10 rating of ten common symptoms (total rating 0-100). In this study, we examined the association between the ESAS score and overall survival (OS) in pts with localized and metastatic GE adenocarcinoma (GEA). Methods: This study is based on the retrospective cohort database of pts with localized (stage I-III) and metastatic GEA. We included pts who were diagnosed with GEA between 2011 and 2021 and completed at least 1 baseline ESAS prior to the treatment. Pts were grouped into 3 cohorts based as follows: High symptom burden (SB) ESAS score ≥ 26, Moderate SB (11-25) or low SB (0-10). OS was defined as time from the first visit date to death. OS was assessed using the Kaplan-Meier method and significance was set at 2-sided P &lt; 0.05. Univariate statistical analyses were used to examine the relationships between OS and multiple variables in the presentation. Results: 233 pts met the inclusion criteria: median age was 60.8y [51.4, 69.4]; 58% of pts were ECOG PS 1; 81% were non-Asian and 18.9% Asian; 67.4% of pts were male and 32.6% female. In terms of tumor location, gastric represented 47.2% of pts, GEJ 40.8% and esophageal 12.0% primaries; 43.7% pts were stage I-III, while 56.3% were de-novo metastatic pts. Median OS in Low, Mod, High SB pts cohorts were 22.7m, 17.6mm, &amp; 14.6m, respectively (p &lt; 0.036). Although worse OS and worse ESAS levels were not statistically significant in the localized pts (p, 505) and metastatic subgroup (p 0,092), there was a numerical tendency, especially in the metastatic pts. In the univariate analysis, there was a significant association between OS and high-symptom burden (Hazard ratio [HR] = 1.64 (95% CI, 1.12-2.38; p = 0.0104), ECOG ≥2 (HR= 2.79 (95% CI, 1.62-4.79; p = 0.0002) and metastatic pts (HR= 3.50 (95% CI, 2.51-4.86, p&lt;0.0001). Conclusions: Higher SB based on ESAS was associated with poorer OS among GEA pts. ESAS is a reliable tool that carries a prognostic significance that could be used in practice.[Table: see text]